Process for the resolution of D,L-racemic mixtures

ABSTRACT

The invention relates to a process for the kinetic resolution of D,L-racemic mixtures of racemates crystallizing as conglomerates. Resolution is effected from supersaturated solutions of these which is carried out in the presence of a polymer bound inhibitor of crystallization of the one form, resulting in the preferred crystallization of the one form, and when the other form is desired - in the presence of such inhibitor for the other form. Amongst racemic mixtures amenable to this process are amino acids. The process can be carried out in a two-compartment device, where the compartments are separated by a membrane which is permeable to the constituents of the racemate, while it is impervious to the polymer-bound inhibitor for the crystallization of one of the racemic forms.

This application is a continuation of application Ser. No. 929,318,filed 11/12/86.

FIELD OF THE INVENTION

The invention relates to a process for the kinetic resolution ofD,L-racemic mixtures of racemates which crystallize as conglomerates.The resolution is effected in the presence of a suitable polymericinhibitor, which consists of a polymer backbone to which there is boundeither the D form of the enantiomers (or of a modified compound) whenthe preferred crystalline form is to be the L-form of the racemate, oran L-form of the enantiomers when the resolved form desired is theD-form. Some of the polymers used for the resolution are novel and formpart of the invention. Furthermore, this invention relates to a processof resolution as set out above, where the conglomerate phase ismetastable.

BACKGROUND OF THE INVENTION

It has been demonstrated that kinetic resolution of racematescrystallizing in the form of conglomerates can be accomplished bycarrying out the crystallization in the presence of small amounts ofresolved additives, the stereochemical molecular structure of whichresembles that of one of the enantiomers of the said racemic mixture.According to that process the non-polymeric inhibitors were added inrather large quantities (up to 10% wt/wt of racemic mixture). Inaddition such additives were occluded in the bulk of the precipitatingcrystals, in typical amounts of 0.5-1.5%. Furthermore, the additivecannot be separated from the precipitating crystals, see U.S. Pat. No.4,533,506, granted Aug. 6, 1985; see also Addadi et al., J. Am. Chem.Soc., 104 4610 (1982).

In the present invention the use of polymeric inhibitors makes itpossible to reduce the quantity of the additive by up to a factor of 10or more.

The invention relates also to a process of resolution as set out above,where the racemate is provided in adjacent compartments of theresolution cell, separated by a suitable membrane, there being added tothe first compartment an inhibitor of D-form crystallization, and to theother compartment an inhibitor of L-form crystallization. The result isthat in one compartment essentially pure L-form enantiomer is obtained,and in the other D-form. This is made possible by the fact that contraryto the simple additives used before, the polymeric forms do not passthrough such membranes.

The invention also relates to this process of separation where atwo-compartment device with a membrane is used and to such separationdevice for this purpose. Various polymers can be used. As example, theinvention is illustrated with reference to certain poly-(N.sup.ε-acryloyl-L- or -D-amino acid) and poly-(N.sup.ε -methacryloyl-D- or-L-amino acid) as the compounds which are used as inhibitors, the aminoacid bound to the polymer being chosen according to the racemate whichis to be resolved.

We have found that addition in solution of poly-(N.sup.ε-acryloyl-L-lysine) (L-PAL) or poly-(N.sup.ε -methacryloyl-L-lysine)(L-PMAL) M.W. or poly-[L-α-glutamyl)N-Acryloyl)hydrazide])L-PGAH) withdifferent molecular weights in 0.1-1% wt/wt to a supersaturated solutionof D,L-glutamic acid.HCl, (Glu.HCl) brings about a preferredcrystallization of D-glutamic acid.HCl (D-Glue.HCl). Similarly, additionof poly-(N.sup.ε -acryloyl-D-lysine) (D-PAL) or the methacryloylanalogue or D-PGAH allows the L-glutamic acid to precipitate.Furthermore, we have found that from a supersaturated aqueous solutionof D,L-asparagine (Asn) addition of (L-PAL) or (L-PMAL) allows thepreferred precipitation of D-asparagine monohydrate, (D-Asn.H₂ O) andthe addition of D-analogue polymers allows the separation ofL-asparagine monohydrate (L-Asn.H₂ O). Similarly, the addition of(L-PAL) or (L-PMAL) in 0.1-1% wt/wt to a supersaturated solution of D,Lthreonine (DL-Thr), brings about preferred crystallization ofD-Threonine (D-Thr). Addition of (D-PMAL) or (D-PAL) leads to preferredcrystallization of L-threonine (L-Thr).

Analogously, poly-(N-acryloyl-(p-aminobenzoyl)-D-secphenethylamide)(D-PA-PAB-PHA) allows the preferential crystallization ofL-sec-phenethylalcohol as its 3,5-dinitrobenzoate from a racemicmixture. Inclusion ofpoly-(N-acryloyl-(p-aminobenzoyl)-L-secphenethylamide) (L-PA-AB-PHA)causes the preferred precipitation of the D-form. Analogously, theaddition of the poly(P-acrylamido-L-phenyl alanine) (L-PA-PhE) orpoly-(acryloxy-L-p-tyrosine) (L-PAO-Tyr) or the correspondingmethacryloyl polymers allow the preferential crystallization ofD-histidine.HCl.H₂ O (D-HIS.HCl.H₂ O) from a racemic mixture both atT>45° C. and T<45° C., where the conglomerate phase is metastable.Further, the addition of poly-(p-acrylamido-D-phenyl alanine) (D-PA-Phe)or poly-(acryloxy-D-p-tyrosine) (D-PAO-Tyr) or the correspondingmethacryloyl polymer allows the preferential crystallization ofL-histadine.HClH₂ O from the racemic mixture. Similarly, the addition of(L-PAL) or (L-PA-Phe) or (L-PMAL) or (L-PAO-Tyr) or the correspondingmethacryloyl polymers allows the preferential crystallization ofD-p-hydroxphenyl-glycine-p-toluenesulphonate (D-pHPGpTS). The additionof any of the same D polymers results in the preferentialcrystallization of L-pHPGpTS. In a similar way, the addition ofpoly-(p-acrylamido-L-α-methyl-phenyl alanine) or the correspondingmethacryloyl polymer allows the preferential crystallization ofD-α-methyl-DOPA (3,4-dihyroxy-α-methyl-phenyl alanine). The addition ofany of the same D polymers allows preferential crystallization ofL-α-methyl-DOPA.

A similar resolution can be effected by using a device comprising twocompartments separated by a membrane, provided with means for agitation.The L-type polymer is in one compartment (A) while the D-type polymer isin the second compartment (B). The polymer cannot diffuse through themembrane while the molecules of the substrate equilibrate (diffusethrough the membrane).

Our previous patent, U.S. Pat. No. 4,533,506 describes that racemicconglomerates can be resolved by small molecular weight additives. Wehave now found that soluble polymers are much more efficient and useful.The fact that the additive is chemically bound to a polymer backbone,taking advantage of the cooperative effect, makes it possible tointroduce the polymer in the desired solution in a very reduced amount(up to 1% wt/wt) of the racemic mixture to be resolved. In addition thepolymer is not occluded in the crystals but remains in solution.Improved resolution, i.e. high chemical and optical yield of the desiredenantiomer is achieved. Since the additive is linked to a polymer ofhigh molecular weight, it allows carrying out the resolution of aracemic mixture in a device of two compartments separated by a membrane.

EXPERIMENTAL

This invention can be used to produce crystalline threonine,asparagine.H₂ O, glutamic acid.HCl, phenethyl alcohol (as its3,5-dinitrobenzoate), histidine HCl.H₂ O and p-hydroxyphenyglycine (asits p-toluenesulphonate salt) enriched in the desired enantiomer, or inits pure enantiomeric form, without requiring the use of seed crystalsof this enantiomer. The use of seed crystals of this enantiomer may,however, be desirable from the point of view of the rate ofcrystallization. For the case where a seed crystal of the desiredenantiomer is used, this invention describes an improvement of theprocess for threonine, asparagine, glutamic acid.HCl, sec-phenethylalcohol, histidine.HCl.H₂ O and pHPGpTS by further addition in solutionof the appropriate polymers for each compound. The following examplesare illustrative to the present invention but are not to be interpretedin a limiting sense.

EXAMPLES 1-23

Glutamic acid.HCL: D,L glutamic acid (D,L-Glu) (1 g) and poly(N.sup.ε-acryloyl-L-lysine) or poly-(N.sup.ε -methacryloyl-L-lysine orpoly-[L-glutamyl)N-Acryloyl)hydrazide] were heated in hydrochloric acid5N (5 ml) at about 60° C. to complete dissolution. The solution wasfiltered, cooled to room temperature with or without agitation and seedcrystals (0.5 mg) of D,L-Glu.HCl added. Crystals formed (20 hrs) wereseparated by filtration and their enantiomeric excess was determined.The conditions and the results are summarized in Tables I and II.

EXAMPLE 24

An experiment for resolution of D,L-glutamic acid.HCl by a devicecomposed of two compartments separated by a membrane is described. Around perspex piece of 9 cm exterior diameter, 6 cm internal diameterand 0.9 cm thickness was connected to another piece of perspex of thesame dimensions via a membrane with cut-off of 10000-15000, andmechanically shaken for 48 h. Into each compartment a solution of 4 gD,L-glutamic acid in 20 ml of HCl 5N was introduced (total 8 g/40 ml).Poly-(N.sup.ε -acryloyl-L-lysine) or poly-(N.sup.ε-methacryloyl-L-lysine) was dissolved in one compartment (A) whilepoly-(N.sup.ε -acryloyl-D-lysine) or poly-(N.sup.ε-methacryloyl-D-lysine) was dissolved in the second compartment (B).Each compartment was seeded with 0.5 mg of D,L-glutamic acid.HCl. After48 h the solid from each compartment was filtered to give fromcompartment (A) 605 mg of D-glutamic acid.HCl with (α)D=-24° C. and fromcompartment (B) 575 mg of L-glutamic acid.HCl with (α)D=+24° C.

EXAMPLES 25-29

Asparagine.H₂ O: A slurry of D,L-Asn.H₂ O (500 mg) and poly-(N.sup.ε-methacryloyl-L-lysine) in water (5 ml) was heated to about 80° C. untilcomplete dissolution occurred. The warm solution was filtered and cooledto room temperature without agitation. After 20 h the separated crystalswere recovered by filtration and the enantiomeric excess was determined.The conditions and results are summarized in Table III.

EXAMPLES 30-38

Threonine: D,L-Threonine (DL-Thr) and poly-(N.sup.ε-methacryloyl-L-lysine) or poly-(N.sup.ε -acryloyl-L-lysine) were heatedin water to about 80° C. until complete dissolution occurred. The hotsolution was filtered and cooled to room temperature. After a definedtime the precipitate was filtered and the enantiomeric excess wasdetermined. The conditions and results are summarized in Table IV.

EXAMPLE-39-48

3,5-Dinitro-sec-Phenethyl Benzoate: A solution of3,5-dinitro-DL-sec-phenethylbenzoate in toluene and a solution ofpoly-(N-acryloyl-(p-amino-benzoyl)-D-sec-phenethylamide) or thepoly-L-analogue in N,N'-dimethyl-formamide were mixed together, heatedto complete dissolution, and seed crystals of3,5-dinitro-DL-sec-phenethylbenzoate (0.5 mg) added. The crystals whichwere formed were separated by filtration, dried and the enantiomericexcess was determined. The results and conditions are summarized inTable V.

EXAMPLES 49-59

Histidine.HCl.H₂ O: D,L-His.HCl.H₂ O (3.2 g) and the appropriate polymerwere slurried in water (5 ml) and the slurry was heated to completedissolution. The hot solution was filtered and allowed to stand at 50°C. for 20 hrs without agitation. The crystals were collected byfiltration and the enantiomeric excess was determined. The results aresummarized in Table VI.

EXAMPLES 60-67

Histidine. HCl.H₂ O: D,L-His.HCl.H₂ O (4.0 g) and the appropriatepolymer were slurried in water (10 ml) and the slurry was heated tocomplete dissolution. The hot solution was filtered, cooled to 25° C.,seeded and allowed to stand without agitation for 3-7 days. The crystalswere collected by filtration and the enantiomeric excess was determined.The results are summarized in Table VII.

EXAMPLES 68-76

pHPGpTS: D,L-pHPGpTS and the appropriate polymer were slurried in 0.5Mp-toluenesulfonic acid in water, and the slurry was heated untilcomplete solution occurred. The hot soluton was filtered and allowed tocool to room temperature without agitation. The crystals were collectedby filtration and the enantiomeric excess was determined. The conditionsand results are summarized in Table VIII.

                  TABLE I                                                         ______________________________________                                        (Glu.HCl). The following examples were carried out without                    agitation:                                                                                    weight*.sup.1  precipitated                                          type of  (%) of   [α]D                                                                          crystals                                                                              chemical*.sup.2                        Example                                                                              polymer  polymer  degree                                                                              e.e.(%) yield %                                ______________________________________                                        1      L-PMAL   3        -23.3 94.7    22.5                                   2      "        3        -23.7 96.3    25.2                                   3      "        2        -24.2 98.4    22.0                                   4      "        1        -23.2 94.3    26.6                                   5      "        1        -24.0 97.5    21.6                                   6      "        1        -24.2 98.4    22.0                                   7      "        0.5      -23.8 96.7    20.3                                   8      "        0.5      -23.6 95.9    26.5                                   9      "        0.1      -11.8 47.9    33.6                                   10     "        0.1      -10.2 41.4    37.2                                   11     L-PAL    3        -24.0 97.5    15.3                                   12     "        1        -23.8 96.7    12.5                                   13     "        0.5      -23.3 94.7    16.1                                   14     "        0.1      -23.8 96.7    11.6                                   15     D-PAL    0.5      +22.9 93.0    15.7                                   16     "        0.1      +23.7 96.3    19.3                                   17     L-PGAH   1.0      -23.7 96.3    18.0                                   18     "        0.8      -24.2 98.4    10.0                                   19     "        0.5      -24.2 98.4    12.0                                   20     D-PGAH   0.8      -24.0 97.5    18.0                                   21     "        0.5      -24.2 98.4    18.0                                   ______________________________________                                         *.sup.1 expressed in weight % of racemic glutamic acid. HCl. This same        notation (weight % of racemic material is used in all the following           tables.                                                                       *.sup.2 the chemical yield is defined as;                                     ##STR1##                                                                      This same notation is used in all the following tables.                  

                  TABLE II                                                        ______________________________________                                        The following experiments were carried out with agitation                     (magnetic stirring).                                                                                            precip-                                                                              chem-                                                   weight         itated ical                                                    (%) of   [α] D                                                                         crystals                                                                             yield                                Example                                                                              type of polymer                                                                           polymer  degree                                                                              e.e. (%)                                                                             %                                    ______________________________________                                        22     L-PMAL      1        -24.2 98.3   20.4                                 23     "           1        -24.0 97.5   22.0                                 ______________________________________                                    

                                      TABLE III                                   __________________________________________________________________________    (Asn.H.sub.2 O)                                                                               precipitated                                                                             conditions                                              weight % of                                                                          [α] D                                                                       crystals                                                                            chemical                                                                           seeded                                             Example                                                                            polymer                                                                              degree                                                                            e.e of                                                                              yield %                                                                            with 0.5 mg of                                     __________________________________________________________________________    25   0.2    -4.3                                                                              14    52.2 DL-Asn.H.sub.2 O                                   26   1      -9.0                                                                              29.5  45.0 DL-Asn.H.sub.2 O                                   27   2      -28.3                                                                             92.7  14.6 D-Asn.H.sub.2 O                                    28   4      -12.0                                                                             39.3  40.0 DL-Asn.H.sub.2 O                                   29   4      -27.7                                                                             90.8  15.6 D-Asn.H.sub.2 O                                    __________________________________________________________________________

                                      TABLE IV                                    __________________________________________________________________________    (Thr.) The following experiments were carried out eith D,L seed               crystals (0.5 mg):                                                                       Vol. of                                                                           Weight % of        precipitated                                      DL-Thr                                                                             H.sub.2 O                                                                         Poly-(N--metha-                                                                           time                                                                             [α] D                                                                       crystals                                                                            chemical                              Example*'                                                                           (gr) (ml)                                                                              cryloyl-L-lysine)                                                                         h  degree                                                                            e.e   yield %                               __________________________________________________________________________    30    0.9  3   3.3         20 +15.0                                                                             95.3  23.1                                  31    1.5  5   1.3         20 +26.6                                                                             94.6  27.6                                  32    0.9  3   1.1         6  +25.7                                                                             91.7  12.6                                  33    1.5  5   1.1         20 +26.9                                                                             96.0  18.4                                  34    0.9  3   0.5         6  +25.3                                                                             90.3  10.0                                  35    0.9  3   0.5         20 +8.0                                                                              28.5  34.2                                  36    1.5  5   0.3         20 +25.8                                                                             92.1  19.0                                  37    0.9  3   0.5         20 +22 78.5  22.2                                  38    0.9  3   1           20 +23.9                                                                             85.3  19.6                                  __________________________________________________________________________     *'Experiments 30-36 were carried out without agitation and experiments        37-38 with agitation.                                                    

                                      TABLE V                                     __________________________________________________________________________    (3,5-Dinitro-D,L-sec-phenethyl benzoate)                                           wt. (gr)                                                                           Vol. of                                                                           Vol. of Weight     precipitated                                      of DL-                                                                             toluene                                                                           DMF Polym                                                                             (%) of                                                                            time                                                                             [α] D                                                                       crystals                                                                            chemical                               Example                                                                            substr.                                                                            (ml)                                                                              (ml)                                                                              config.                                                                           polym                                                                             h  degree                                                                            e.e.  yield %                                __________________________________________________________________________    39   1.4  0.5 1   D   2   5  +37.5                                                                             97.4  6.4                                    40   1.5  0.5 1   D   1   7.5                                                                              +38.5                                                                             100   10                                     41   1.5  0.5 1   D   1   11 +33.5                                                                             87    15                                     42   1.5  0.5 1.5 D   3   24 +38.5                                                                             100   14                                     43   1.5  0.5 1   D   0.2 5  +5  13    8.6                                    44   4.5  0.5 3   D   1   8  +38.5                                                                             100   11.2                                   45   1.5  0.5 1       None                                                                              3.5                                                                              0   0     22                                     46   1.5  0.5 1   L   1   7  -38.5                                                                             100   9.5                                    47   1.5  0.5 1.5 L   2   18 -38.5                                                                             100   11                                     48   1.5  0.5 1   L   1.5 6  -38.0                                                                             98    7                                      __________________________________________________________________________

                                      TABLE VI                                    __________________________________________________________________________    (His.HCl.H.sub.2 O)                                                                wt % type                   precipitated                                      of   of    polym.                                                                            seeding  [ α] D                                                                      crystals                                                                            chemical                               Example                                                                            polymer                                                                            polymer                                                                             config.                                                                           with     degree                                                                            e.e.  yield %                                __________________________________________________________________________    49   1    PA-Phe                                                                              L   No       -8.8                                                                              91.6  6.9                                    50   1    "     L   D-His.HCl.H.sub.2 O                                                                    -9.6                                                                              100   10                                     51   1    "     L   D-His.HCl.H.sub.2 O                                                                    -9.1                                                                              94.7  11                                     52   1    "     D   L-His.HCl.H.sub.2 O                                                                    +9.6                                                                              100   10                                     53   1    PAO--Tyr                                                                            L   D-His.HCl.H.sub.2 O                                                                    -9.6                                                                              100   8.4                                    54   1    "     L   D-His.HCl.H.sub.2 O                                                                    -9.6                                                                              100   8.3                                    55   1    "     D   L-His.HCl.H.sub.2 O                                                                    +9.2                                                                              95.8  8.5                                    56   0    --    --  D-His.HCl.H.sub.2 O                                                                    -0.9                                                                              9.3   11                                     57   0    --    --  L-His.HCl.H.sub.2 O                                                                    +0.8                                                                              8.3   10.3                                   58   10   PMAL  L   D-His.Hcl.H.sub.2 O                                                                    -4.8                                                                              50    19.0                                   59   10   PMAL  D   L-His.HCl--H.sub.2 O                                                                   +5.8                                                                              50    12.0                                   __________________________________________________________________________

                                      TABLE VII                                   __________________________________________________________________________    (His.Hcl.H.sub.2 O)                                                                wt % type                  precipitated                                       of   of   Polym.                                                                            seeding  [α] D                                                                       crystals                                                                            chemical                                Example                                                                            polymer                                                                            polymer                                                                            config.                                                                           with     degree                                                                            e.e. %                                                                              yield (%)                               __________________________________________________________________________    60   2    PA--Phe                                                                            L   D-His.HCl.H.sub.2 O                                                                    -9.6                                                                              100   15                                      61   2    PA--Phe                                                                            D   L-His.HCl.H.sub.2 O                                                                    +9.6                                                                              100   15                                      62   2    PAO--Tyr                                                                           L   D-His.HCl.H.sub.2 O                                                                    -9.6                                                                              100   15                                      63   2    PAO--Tyr                                                                           D   L-His.HCl.H.sub.2 O                                                                    +9.6                                                                              100   15                                      64   3    PA--Phe                                                                            L   DL-His.HCl.H.sub.2 O                                                                   -9.6                                                                              100   13                                      65   3    PA--Phe                                                                            D   DL-His.HCl.H.sub.2 O                                                                   +9.6                                                                              100   13                                      66   3    PAO--Tyr                                                                           L   DL-His.HCl.H.sub.2 O                                                                   -9.6                                                                              100   13                                      67   3    PAO--Tyr                                                                           D   DL-His.HCl.H.sub.2 O                                                                   +9.6                                                                              100   13                                      __________________________________________________________________________

                                      TABLE VIII                                  __________________________________________________________________________    (PHPGpTS)                                                                          D L   weight                      precipitated                                PHpGpTS,                                                                            % of                                                                              type of                                                                            polym                                                                             seeding                                                                              Time                                                                             [α ]                                                                         crystals                                                                            chemical                         Example                                                                            gr/ml*                                                                              polym                                                                             polymer                                                                            config                                                                            with   h  degree                                                                             e.e.  yield %                          __________________________________________________________________________    68   0.4/2 1.2 PMAL L   No     20 -65.7                                                                              97.6  13.2                             69   0.4/2 5   "    D   No     20 +65  96.5  12.2                             70   0.5/2 2.5 "    L   No     20 -38.5                                                                              57.2  25.8                             71   0.5/2 2.5 "    L   D-PHPGpTS                                                                            20 -24.0                                                                              35.7  32.4                             72   0.5/2 2.5 "    L   "      20 -59.7                                                                              88.7  22.8                             73   1.4/4 1   PA--Phe                                                                            L   "      2  -66  98.0  16.5                             74   1.4/4 1   "    D   L-PHPGpTS                                                                            2  +67.2                                                                              99.8  10.0                             75   1.4/4 1.5 "    L   DL-PHPGpTS                                                                           2  -25  37.1  27                               76   1.4/4 1   "    L   DL-PHPGpTS                                                                           2  -33  49.0  21                               __________________________________________________________________________     *'A solution of 0.5 N of ptoluenesulfonic acid in water.                 

We claim:
 1. A process for the kinetic resolution of D,L racemicmixtures of compounds crystallizing in the form of conglomerates fromsupersaturated solutions of same, which comprises effecting thecrystallization in the presence of an effective quantity of an inhibitorof the crystallization of one form, chemically bound to a polymer, thuspromoting the preferred crystallization of the other form.
 2. A processaccording to claim 1, where the conglomerate form is metastable and thepolymer is an inhibitor of the stable racemic form as well.
 3. A processaccording to claim 1, whenever effected in a system comprising twocompartments separated by a membrane permeable to the constituents ofthe racemate, yet impermeable to the polymer-bound moieties, where inone compartment there is located a polymer bound L-inhibitor inhibitingthe crystallization of the L-form, and in the other a poly D-analogueinhibiting the crystallization of the D-form.
 4. A process according toclaim 1, for resolution of a mixture of D-and L-glutamic acidhydrochloride which comprises forming a supersaturated solution of saidmixture, adding poly-(N.sup.ε -acryloyl-L-lysine) or poly-(N.sup.ε-methacryloyl-L-lysine) or poly-[L-2-glutamyl-(N-acryloyl)hydrazide] asan inhibitor of the L-amino acid when D-amino acid is desired, or asimilar additive in the D-form when the L-form is desired, andcrystallizing part of the desired form from said supersaturatedsolution.
 5. A process according to claim 4, whenever effect in amembrane-separated two-compartment system.
 6. A process according toclaim 1, for resolution of a mixture of D- and L-forms of asparagine,which comprises forming a supersaturated solution of said mixture,adding poly-(N.sup.ε -acryloyl-L-lysine) or poly-(N.sup.ε-methacryloyl-L-lysine) as crystallization inhibitor of the L-form ofasparagine when the D-form of asparagine is desired, or adding theD-form of one of these polymers when the L-form of asparagine isdesired, and crystallizing a part of the desired form of asparagine fromsaid supersaturated solution.
 7. A process according to claim 1 for theresolution of a mixture of D- and L- forms of threonine which comprisesforming a supersaturated solution of said mixture, adding poly-(N.sup.ε-acryloyl-L-lysine) or poly-(N.sup.ε -methacryloyl-L-lysine) as acrystallization inhibitor of the L-form of threonine when the D-form ofthreonine is desired, or adding the D-form of the polymer when theL-form of threonine is desired, and crystallizing a part of the desiredform of threonine from said supersaturated solution.
 8. A processaccording to claim 1, for resolution of a mixture of D- and L-histidineHCl which comprises forming a supersaturated solution of said mixture,adding poly-(N.sup.ε -acryloyl lysine) or poly-(N.sup.ε-methacryloyl-L-lysine) or poly-(p-acrylamido-L-phenyl alanine) orpoly-(p-acryloxy-L-tyrosine) as an inhibitor of the crystallization ofthe L-amino acid when the D-amino acid is desired or an analogouspolymeric additive in the D-form when the L-form is desired, andcrystallizing part of the desired form of the compound from saidsupersaturated solution, at a temperature of 45° C. or above.
 9. Aprocess according to claim 1, for resolution of a mixture of D- andL-histidine HCl which comprises forming a supersaturated solution ofsaid mixture, adding poly-(p-acrylamido-L-phenyl alanine) orpoly-(p-acryloxy-L-tyrosine) as an inhibitor of L amino acid when theD-amino acid is desired or an analogous polymeric additive in D-formwhen the L-form is desired, and crystallizing part of the compound fromsaid supersaturated solution at a temperature of 45° C. or below.
 10. Aprocess according to claim 1, wherein also seed crystals of desired formof His. HCl.H₂ O are added during the crystallization step.
 11. Aprocess according to claim 1 for a resolution of a mixture of D andL-pHPGpTS which comprises forming a supersaturated solution of saidmixture, adding poly-(N.sup.ε -acryloyl-L-lysine) orpoly-(p-acrylamido-L-phenyl alanine) or poly-(p-acryloxy-L-tyrosine) asan inhibitor of the L-amino acid when the D-amino acid is desired, or ananalogous polymeric additive in the D-form when the L-form is desired,and crystallizing the desired compound from said supersaturatedsolution.
 12. A process according to claim 1 for resolution of a mixtureof D- and L-forms of 3,5-dinitro-sec-phenethylbenzoate, which comprisesforming a supersaturated solution of said mixture, addingpoly-[N-acryloyl-(p-aminobenzoyl)-D-sec-phenethylamide] or themethacryloyl analog as crystallization inhibitor of the D-form of3,5-dinitro-sec-phenethylbenzoate when the L-form is desired, or addingthe L-form of these polymers when the D-form of3,5-dinitro-sec-phenethylbenzoate is desired and crystallizing thedesired compound from said supersaturated solution.
 13. A process inaccordance with claim 1, wherein said polymer is a polyacrylic acid or apolymethacrylic acid.
 14. A process in accordance with claim 3, whereinsaid polymer is a polyacrylic acid or a polymethacrylic acid.
 15. Aprocess in accordance with claim 1, wherein said D,L racemic mixtures ofcompounds crystallizing in the form of conglomerates from supersaturatedsolutions of same is selected from the group consisting of racemicmixtures of D- and L-glutamic acid hydrochloride, D- and L-forms ofasparagine, D- and L-forms of threonine, D- and L- histidine HCl, D andL-pHPGpTS and D- and L-forms of 3,5-dinitro-sec-phenethylbenzoate.